CN1278528A - Process for preparation of 5,6-dihydroxyl-2-amino-1,2,3,4-tetrahydronaphthalene derivatives - Google Patents

Abstract

A process, and variations thereof, for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivatives of formula (I), wherein R1, R2, R3 can independently be hydrogen or lower alkyl.

Description

Process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetralin derivatives

式中R₁，R₂和R₃，可以相同或不同，是氢或者直链或支链低级烷基。The present invention relates to a kind of preparation structure formula (I) 5,6-dihydroxy-2-amino-1,2,3,4-tetralin (or amino-1,2,3,4-tetrahydronaphthalene) ( 5,

In the formula, R ₁ , R ₂ and R ₃ , which may be the same or different, are hydrogen or straight or branched lower alkyl.

Amino-1,2,3,4-tetralin is a compound with pronounced sympathomimetic activity.

Due to their properties, these compounds can be used in different therapeutic fields as drugs active on the bronchial, cardiovascular, renal and central nervous systems.

Many methods for the preparation of 5,6-ADTN are disclosed in literature and patents since the late sixties.

Certain syntheses require the preparation of 5,6-dimethoxy-1-tetralone, which is then converted to 5,6-ADTN by various methods: via 5,6-dimethoxy-1-tetrahydro Neber rearrangement of naphthalenone O-tosyl oxime (W.K. Sprenger et al., J.Med.Chem., 12, 487, 1969, improved by J.C.Kim et al., J.Kor.Chem.Soc., 21 (3), 187, 1977), by α-bromination treatment and subsequent substitution of bromine (J.C.Kim et al., J.Kor.Chem.Soc., 20, 91, 1976; Y.Oka et al., Chem.Pharm. Bull., 25(4), 632, 1977). By α-nitrosation and subsequent reduction (Y. Oka et al., Chem. Pharm. Bull., 25(4), 632, 1977).

Certain syntheses require the preparation of 5,6-dimethoxy-2-tetralone, which is then converted to the corresponding 2-amino derivative by reductive amination (J.D.McDermed et al., J.Med .Chem., 18(4), 362,1975; J.G.Cannon et al., J.Med.Chem., 20(9), 1111,1977; U.S. Patent US 646300 (IowaUniv.)), or by converting it into The corresponding o-methyloxime is then reduced again (J.G.Cannon et al., J.Med.Chem., 17(5), 565, 1974).

Certain syntheses are based on the preparation of 5-hydroxy-6-methoxy-1,2,3,4,-tetrahydro-2-naphthoic acid followed by Curtis rearrangement into 5,6-ADTN (K. Mitsuhashi et al., Chem. Pharm. Bull., 20(6), 1321, 1972).

The only enantiospecific synthesis of 5,6-ADTN is based on the use of 2,2-dimethyl-3-methoxycarbonyl-oxazolidin-4-aldehyde (A.D. Baxter et al., Tetrahedron Letters, 33( 17), 2331, 1992).

All these methods are severely limited for industrial application.

At present, the method for preparing 2-amino-5,6-dimethoxy-1,2,3,4-tetralin which is industrially acceptable has been claimed in EP-A-0534536 (September 17, 1991 date of application, the applicant is Zambon).

According to the latter reference, 5,6-dimethoxy-2-amino-1,2 , 3,4-Tetralin. Start by condensing 2,3-dimethoxybenzaldehyde with pyruvic acid to obtain tetralone (step A), convert the ketone group into amino and reduce unsaturated amino acids (step B), and then carry out intramolecular cyclization The desired 5,6-dimethoxy-2-amino(protected)-1-tetralone is obtained.

Hudson et al. (J.Chem.Soc., 715-722 (1941)) and Pavel et al. (ActaUniv.Palacki Olomuc.Fac.Rerum.Natur., 401-404 (1971)) have already disclosed this condensation reaction ( Step A).

In this regard, EP0534536 emphasizes that in the presence of inorganic bases, such as sodium hydroxide (Hudson) or potassium carbonate (Pavel), the yields of this reaction are very low (40% and 6%, respectively), so that it does not have significance for industrial applications.

In the aforementioned EP0534536, the problem of low yield was solved by carrying out the condensation reaction in the presence of an organic base such as triethylamine, piperidine, piperazine and morpholine. The condensation product can be obtained in yields of up to about 80%. The condensation reactions described here require special reaction conditions such as anhydrous organic solvents (dimethylformamide is indicated), an inert atmosphere, and low temperatures during addition of reagents. Recovery of the product requires an extraction step to remove the organic solvent.

From the point of view of industrial application, the above-mentioned condensation reactions have additional cost expenditures for reagents, anhydrous solvents and equipment requirements.

It has now been found that the condensation of 2,3-dialkoxybenzaldehyde and pyruvic acid in the presence of an inorganic base in an aqueous/alcoholic solvent gives 4-(2,3-dialkoxyphenyl) in high yield -2-ketobutenoic acid. The reaction is carried out at room temperature.

The present invention provides a method for preparing 5,6-dihydroxy-2-amino-1,2,3,4-tetralin derivatives of formula I and their acid addition salts:

Wherein R ₁ , R ₂ and R ₃ can be the same or different, and are hydrogen or C ₁ -C ₄ alkyl, the method comprises the following steps:

(a) the keto group at the 2-position of 2-keto-4-(2,3-dialkoxyphenyl)butenoic acid is converted or replaced into amino, alkylamino or alkoxycarbonylamino to obtain the formula Compound of II

Wherein _R'1 is hydrogen, alkyl or alkoxycarbonyl, _R2 and _R3 are hydrogen or alkyl;

b) intramolecular cyclization to obtain 5,6-dihydroxy or 5,6-dialkoxy-2-amino or 2-alkylamino or 2-alkoxycarbonylamino-1-tetralone of formula III

wherein _R1 ' is hydrogen, alkyl or alkoxycarbonyl and _R2 and _R3 are hydrogen or alkyl;

其中R′₁是氢，烷基或烷氧羰基，R₂和R₃是氢或烷基。本发明的一个方面提供一种用于制备结构式(I)化合物的方法：该方法包括：c) reduction of the keto group to obtain 5,6-dihydroxyl/5,6-dialkoxy-2-amino/2-alkylamino/2-alkoxycarbonylamino-1,2,3 of formula IV, 4-tetralin

wherein _R'1 is hydrogen, alkyl or alkoxycarbonyl, and _R2 and _R3 are hydrogen or alkyl. One aspect of the present invention provides a method for the preparation of compounds of structural formula (I): The method includes:

(a) Condensation of 2,3-dialkoxybenzaldehyde with pyruvic acid in water/alcohol system and presence of inorganic base to give 2-keto-4-(2,3-dialkoxybenzene base)-butenoic acid;

(b) the keto group of the acid is converted into amino or alkylamino, and the double bond is reduced simultaneously to obtain 2-amino or 2-alkylamino-4-(2,3-dialkoxyphenyl) respectively butyric acid;

(c) converting 2-amino or 2-alkylamino-4-(2,3-dialkoxyphenyl)butanoic acid into 4-(2-(2,3-dialkoxyphenyl)ethyl base)-N-alkyl-2,5-oxazolidine-dione;

(d) Cyclization of N-carboxyl anhydride by Friedel-Craft intramolecular acylation in the presence of a Lewis acid, the unprotected 5,6-dialkoxy-2-alkylamino- 1-tetralone;

(e) catalytic reduction of the ketone to 5,6-dialkoxy-2-alkylamino-1,2,3,4-tetralin, and (if desired)

(f) O-dealkylation of the 5,6-dialkoxy-2-alkylamino-1,2,3,4-tetralin gives 5,6-dihydroxy-2-alkane Amino-1,2,3,4-tetrahydronaphthalene.

The steps of the method can be reduced by using halo hydric acid or Lewis acid under suitable conditions, and the unprotected 5,6-dihydroxy-2-alkylamino- 1-tetralone.

On the other hand, the method of the present invention comprises above-mentioned steps (a) and (b), then:

(c) cyclization of 2-alkylamino-4-(2,3-dialkoxyphenyl) butanoic acid and dealkylation on oxygen, then one step directly obtains 2-alkylamino-5, 6-dihydroxy-1-tetralone;

(d) Catalytic reduction of the ketone to obtain 5,6-dihydroxy-2-alkylamino-1,2,3,4-tetralin hydrochloride.

The resulting final compound is usually in the form of a salt, but the process of the invention also makes it possible to convert the derivative into the free base or into another acid addition salt.

Examples of lower alkyl groups are linear or branched C ₁ -C ₄ alkyl groups.

In a preferred embodiment, the present invention provides a process for the preparation of compounds of formula (I) wherein R ₁ is methyl and R ₂ and R ₃ are H.

According to the first scheme of the present invention, the compound of structural formula (I) is prepared according to the following reaction scheme I:

Reaction Diagram 1

Each step is detailed below.

The first step : the condensation reaction of 2,3-dimethoxybenzaldehyde and pyruvic acid has long been known from the above documents.

According to the present invention, the reaction is carried out using an inorganic base (preferably commercially available potassium hydroxide) in a water/alcohol medium (preferably a water/ethanol medium), and the reaction yield is 80%.

Other inorganic bases that can be used in the present invention are, for example, sodium hydroxide.

Second step : This step involves the conversion of the ketone to an alkylamino group by reductive amination. This transformation is carried out in a single step using a suitable alkylamine (eg aqueous methylamine) and a suitable reducing system (eg catalytic hydrogenation in methanol (catalyst Pd)) using conventional procedures. The reaction was carried out simultaneously with a double bond reduction step with a yield of 60%. The reaction uses methylamine or other alkylamines and thus directly gives 2-amino-1,2,3,4-tetralin derivatives which have been substituted at the amino group with an alkyl group, which can then be optionally substituted. The medium is an alcoholic or hydroalcoholic solution in order to meet the conditions of convenience and cost savings.

Amino acids are available as hydrochloride salts and natural amino acids (zwitterions).

The process can also be carried out with ammonia instead of alkylamines to give 2-amino-1,2,3,4-tetralins unsubstituted on the amines.

The third step : by conventional method (Cfr.ARKatritzky, CWReesComprehensive Heterocyclic Chemistry, Part 4B, the 231st page, 1984, Pergamon Press; JP Greenstein, M.Winitz Chemistry of the AminoAcids, Vol.2, 867-868 pages, 1961 and ref .cit.), a one-step conversion of an amino acid to the corresponding cyclic N-carboxy anhydride using phosgene.

For practical purposes, the reaction is preferably divided into two steps:

- using a suitable chloroformate (such as benzyl chloroformate or ethyl chloroformate) to convert 2-alkylamino-4-(2,3-dialkoxyphenyl)butanoic acid in quantitative yield Amino groups are converted to carbamates;

- 4-(2,3-dialkoxyphenyl)-2-(N-alkyl-N-alkoxycarbonylamino)butanoic acid ring, for example with thionyl chloride, in the absence or presence of an organic solvent Formation of cyclic N-carboxy anhydrides with simultaneous removal of alkyl halides. The yield is close to quantitative.

The resulting product is solid, stable and easy to handle without special handling. So far, we know that the use of this specific anhydride in the preparation of compounds having the structure of amino-1,2,3,4-tetralin has not been reported in the literature.

This method allows direct access to 2-alkylamino-5,6-dialkoxy-1-tetralones in subsequent steps, eliminating the need for protection/deprotection of the amino group, as opposed to what is required in EP00534536 .

Fourth step : This step involves subjecting 4-(2-(2,3-dialkoxyphenyl)ethyl)-N-alkyl-2,5-oxazolidinedione to Friedel-Craft Intramolecular acylation of Fu, then obtains 5,6-dialkoxy-2-alkylamino-1-tetralone, this step is carried out according to conventional procedures, such as using aluminum trichloride or in anhydrous aprotic Other suitable Lewis acids (eg BBr ₃ , BCl ₃ , SnCl ₄ , TiCl ₄ ) in a transfer solvent (preferably chlorinated).

The fifth step : in a water-containing or water-alcoholic medium, use hydrochloric acid as an acid, and use palladium/carbon as a catalyst to reduce 5,6-dialkoxy-2-alkylamino-1-tetralone to 1, 2,3,4-Tetralin. The yield is close to quantitative.

The sixth step : 5,6-dialkoxy-2-alkylamino-1,2,3,4-tetralin is subjected to a possible O-dealkylation reaction using conventional procedures to obtain 5,6- Dihydroxy-2-alkylamino-1,2,3,4-tetrahydronaphthalene, e.g. using a suitable concentrated halogenated hydrogen-containing acid (e.g. HBr in water) or in an aprotic nonpolar solvent (e.g. trichloride Aluminum in anhydrous toluene) with the appropriate Lewis acid, the reaction yields are close to quantitative.

In the second scheme of the present invention, the compound of structural formula (I) is prepared according to the following reaction scheme 2: reaction scheme 2

Each step is detailed below:

Method 2

First and second steps : carry out the first and second steps according to the procedures described in the first and second steps of method 1.

Third step : This step involves cyclization by intramolecular acylation of amino acids with simultaneous deprotection of the catechol hydroxyl groups. The reaction is carried out using a concentrated halogenated hydroacid such as 48% hydrobromic acid at reflux, 37% hydrochloric acid or 57% hydroiodic acid under pressure at a temperature of 100-140°C. The reaction may also employ a suitable Lewis acid in an aprotic solvent (eg _BBr3 in dichloromethane). This step is especially important.

In fact, so far, to the applicant's knowledge, there is no description in the literature of a method capable of obtaining intramolecular cyclization in one step while deprotecting the hydroxyl group, which eliminates the protection and deprotection steps of amino or alkylamino groups .

In fact, the commonly described methods consist of a) protection of the amino group and cyclization according to Friedel-Crafts, either in one step using trifluoroacetic anhydride in trifluoroacetic acid (see EP0534536) or in multiple (see references cited in EP0534536 and A.D.Baxter et al. Tetrahedron Letters, 33(17), 2331, 1992); b) deprotect the amino group; c) deprotect the hydroxyl group (usually treated with hydrobromic acid ); d) possible N-alkylation of 2-amino-1,2,3,4-tetralin.

In addition, the method of the present invention is of particular interest to the industry due to its high yield (approximately 90%) and low reagent costs.

When an acid other than hydrochloric acid is used, the product is simply converted to the hydrochloride by treatment with concentrated hydrochloric acid to obtain the desired quantitative salification.

Using this method it is also possible to start from the amino acid of the optical form to obtain the corresponding symmetric form of 2-(alkyl)amino-5,6-dihydroxy-1-tetralone.

The fourth step : This step involves the reduction of 2-alkylamino-5,6-dihydroxy-1-tetralone by catalytic hydrogenation to obtain 2-alkylamino-5,6-dihydroxy-1,2,3 , 4-Tetralin. The reaction is carried out in water-containing or water-alcoholic medium, the acid used is hydrochloric acid, and palladium-coated carbon is used as a catalyst. The yield is close to quantitative.

According to the method of the present invention, including the above-mentioned modification to it, the 5,6-dihydroxyl-2-amino-1,2,3,4-tetralin substituted with an alkyl group on the amine can be directly obtained, This group is then optionally substituted.

In the first variant, the method provides for the use of N-carboxy anhydrides, which have two functions, namely protecting the amine and activating the carboxyl group, through subsequent cyclization, whereby 5,6-dimethoxy or 5 , 6-dihydroxy-2-methylamino-1-tetralone, omitting the amine deprotection step.

The second version of the method of the present invention is more advantageous, because only in two steps just can obtain 5,6- Dihydroxy-2-alkylamino-1,2,3,4-tetrahydronaphthalene, one of the two steps is cyclization and simultaneous dealkylation of the catechol group, while the other step is reduction.

As far as we know, this is to get 5,6-dihydroxy-2-(alkyl)amino-1,2,3,4-tetralin, especially 5,6-dihydroxy-2-methylamino- The simplest and most direct method for 1,2,3,4-tetralin.

其中的R₁是甲基。According to the third scheme of the present invention, prepare the compound of structural formula (I) according to following reaction scheme 3: Reaction scheme 3

Wherein R ₁ is a methyl group.

The method includes:

(a) Condensation of 4-(2,3-dialkoxyphenyl)-2-ketobutenoic acid with lower alkyl carbamate gives 5-(2,3-dialkoxyphenyl )-3-alkoxycarbonylamino-2,5-dihydrofuran-2-one;

(b) reducing the condensation product to obtain 4-(2,3-dialkoxyphenyl)-2-alkoxycarbonylaminobutyric acid;

(c) Intramolecular cyclization then obtains 5,6-dialkoxy-2-alkoxycarbonylamino-1-tetralone;

(d) reducing the keto group to obtain 5,6-dialkoxy-2-alkoxycarbonylamino-1,2,3,4-tetralin;

(e) Reduction of the carbamate yields 5,6-dialkoxy-2-methylamino-1,2,3,4-tetralin in principle.

Each step is detailed below.

First step : This step involves the condensation of 4-(2,3-dialkoxyphenyl)-2-oxo-3-butenoic acid together with a suitable alkyl carbamate (eg methyl carbamate) , the reaction is carried out in an anhydrous organic solvent in the presence of a catalyst (such as p-toluenesulfonic acid), thus introducing the substituted amino group in one step. The yield of this reaction is close to quantitative.

Second step : This step comprises the use of a catalyst (e.g. palladium on carbon) to convert 3-alkoxycarbonylamino-5-(2,3-dialkoxyphenyl)-2,5-dihydrofuran- The 2-ketone is subjected to catalytic hydrogenation, thus giving 2-alkoxycarbonylamino-4-(2,3-dialkoxyphenyl)butanoic acid. The yield of this reaction is close to quantitative.

The reduction reaction of dehydroamino acid 3-alkoxycarbonylamino-5-(2,3-dialkoxyphenyl)-2,5-dihydrofuran-2-one can be carried out under enantioselective conditions, Thus, the optically active 2-alkoxycarbonylamino-4-(2,3-dialkoxyphenyl)butanoic acid is obtained, whereby another advantage of the present invention can be obtained. For example, by asymmetric hydrogenation, especially using as catalyst a suitable transition metal complex complexed with an optionally active ligand, see Synthesis of Optically Active α-Amino Acids by R.M.Williams pp. 230-256 Page (published by Pergamon Press) and cited references.

The third step : this step includes the cyclization of 2-alkoxycarbonylamino-4-(2,3-dialkoxyphenyl)butanoic acid to obtain 2-alkoxycarbonylamino-5,6-di Alkoxy-1-tetralones. The intramolecular acylation reaction is carried out according to conventional procedures, for example by heating, using solvent-free polyphosphoric acid, another example is using _PCl5 and tin tetrachloride or other Friedel-Grade in a suitable solvent at room temperature. Rifle catalyst (the second procedure is preferred in the case of cyclization of optically active products to obtain the corresponding enantiomer of the tetralone).

The yield of this step is also close to quantitative.

The fourth step : Carry out the reduction reaction according to conventional procedures, for optically active compounds, for example, catalytic hydrogenation can also be used (see the above method). Yields are also close to quantitative.

Fifth step : This step involves the reduction of an alkyl carbamate group (in particular a methoxycarbonylamino group) to a methylamino group using a stoichiometric amount of a suitable reducing agent, in particular is lithium aluminum hydride in a suitable solvent such as tetrahydrofuran. The method has good yields (60-70%) and can also be applied to optically active compounds to give 5,6-dialkoxy-2-alkylamino-1,2,3,4-tetralin corresponding enantiomers of .

Sixth step : This step involves deprotection of the catechol group by conventional (and enantioselective) procedures, for example with concentrated hydrobromic acid and heating, then 5,6-dihydroxy-2-methylamino- 1,2,3,4-tetralin, the yield is close to quantitative.

The procedure of this scheme is more difficult to control and longer than that of the previous scheme, but this procedure can obtain very high yields and is also suitable for obtaining optically active compounds.

The fourth procedure (scheme) is carried out in four steps, starting from 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid and suitable for obtaining 5,6- Dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene. This fourth method is split into two substantially identical parallel routes (A and B).

According to route A, prepare the compound of structural formula (I) by following reaction scheme (4): Reaction scheme 4

The method includes the following steps:

(a) Condensation of 4-(2,3-dialkoxyphenyl)-2-oxo-3-butenoic acid with benzyl carbamate gives 3-benzyloxycarbonylamino-5-(2 , 3-dialkoxyphenyl)-2,5-dihydrofuran-2-one;

(b) Catalytic reduction of 3-benzyloxycarbonylamino-5-(2,3-dialkoxyphenyl)-2,5-dihydrofuran-2-one and simultaneous deprotection to obtain 2-amino -4-(2,3-dialkoxyphenyl)butanoic acid;

(c) cyclization with HBr and simultaneous deprotection gives 5,6-dihydroxy-2-amino-1-tetralone;

(d) Reducing 2-amino-5,6-dihydroxy-1-tetralinone to obtain 2-amino-5,6-dihydroxy-1,2,3,4-tetralin.

Each step is detailed below:

First step : This step involves the condensation of 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid together with benzyl carbamate. The reaction is carried out in an anhydrous organic solvent with a catalyst (such as p-toluenesulfonic acid), so the protected amino group is introduced in one step. The yield of this reaction is close to quantitative.

Second step : This step involves the catalytic hydrogenation of 3-benzyloxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one, e.g. in an alcoholic medium Palladium-on-carbon is used as a catalyst, so deprotected 2-amino-4-(2,3-dimethoxyphenyl)butyric acid can be directly obtained in one step. The yield of this reaction is close to quantitative. As discussed above, this reaction can also be performed under enantioselective conditions to give 2-amino-4-(2,3-dimethoxyphenyl)butanoic acid as the optical form.

The third step : this step includes the cyclization of the intramolecular acylation of the amino acid, and at the same time deprotects the catechol hydroxyl group to obtain 5,6-dihydroxy-2-amino-1-tetralone. The reaction is carried out, for example, using a suitable halogenated hydroacid such as 48% heated hydrobromic acid. The yield of the reaction was high (about 80%).

The fourth step : this step comprises, for example, reducing 2-amino-5,6-dihydroxy-1-tetralone by catalytic hydrogenation using palladium-on-carbon as a catalyst in an aqueous or hydroalcoholic medium to obtain 2-amino- 5,6-Dihydroxy-1,2,3,4-tetrahydronaphthalene. The yield is close to quantitative.

On the other hand, according to route B, in the first step, under the same conditions, 4-(2,3-dimethoxyalkylphenyl)-2-oxo-3-butenoic acid and alkyl carbamate (e.g. methyl carbamate) are condensed together.

The second step comprises reacting 3-alkoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one under the conditions described in the second step of method 3 Catalytic hydrogenation.

The third step involves the cyclization of the intramolecular acylation of the amino acid with deprotection of both the catechol hydroxyl and amino groups to give 5,6-dihydroxy-2-amino-1-tetralone.

The fourth step is carried out as described in Reaction Scheme 4 above.

This method is of particular interest to industry because of its high yields, ease of operation, and low reagent cost, although it is limited to obtaining 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydrogenated naphthalene.

It should be noted that, as is known in the literature, catechol groups are particularly labile, especially in alkaline media, thus requiring the use of protecting groups or salification. This involves formidable difficulties, for example when an organic salt of the product is desired.

The following examples illustrate the invention. Example 1 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid

Put 300ml of deionized water and 50g of potassium hydroxide in a 3 liter flask. The mixture was stirred until dissolved, then 150 ml of ethanol and 100 g of 2,3-dimethoxybenzaldehyde were added. Thereafter, 60.0 g of pyruvic acid was added dropwise thereto (within about 30 minutes) and the mixture was stirred at a temperature of 35-40° C. for about 15 minutes, then poured into 6500 ml of water and brought to a noticeably darker state with about 140 ml of concentrated HCl. acidic pH. The mixture was cooled with stirring for about 30 minutes, then washed with water filtered and dried under vacuum at 60°C to give an orange solid. Yield: 115 g, 80 mole %, 115 weight %; TLC (analysis by thin layer chromatography): dichloromethane/methanol/acetic acid 80/20/2; R _f : 0.5; MP (melting point): 136 -138°C. Example 2 2-methylamino-4-(2,3-dimethoxyphenyl)butyric acid hydrochloride

Put 70.0 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid (0.30 mol) dissolved in 700 ml of ethanol into the hydrogenator, and then add 43.0 g of 8.03M (0.34 mol) methylamine solution and glacial acetic acid to pH 8-9, keeping the temperature below 25°C. Stirring was continued for about 15 minutes, and then 14.0 g of Pd/C (about 50% humidity) was added and reacted under hydrogen pressure (40 psi, room temperature) for 6 hours. The mixture was then brought to a markedly acidic pH with concentrated HCl, filtered and the solution evaporated to dryness. The resulting solid was removed and triturated with 300 ml of acetone under heat (50°C), after which it was cooled with stirring, filtered and dried under vacuum at 40°C. Yield: 51 g, 60% (mole), 73% (weight); TLC: dichloromethane/methanol/acetic acid 75/20/10; R _f =0.5; developing solvent: ninhydrin. MP = 165-166°C. Example 3 4-(2,3-dimethoxyphenyl)-2-(N-methyl-N- benzyloxycarbonylamino )butanoic acid

Put 14.0 g of α-methylamino-4-(2,3-dimethoxyphenyl) butyrate hydrochloride (0.048 mol) and 24 ml of 4N NaOH into a 250 ml flask, and cool the resulting solution to about 0 °C , then, simultaneously but separately dropwise added 9.1 g benzyl chloroformate (0.053 mol) and 13.5 ml 4N NaOH to the solution to keep the solution slightly alkaline, cooled to T<20° C., and then at room temperature Leaves on for about 2 hours. The reaction mixture was diluted with methanolic HCl, washed with 100 ml diethyl ether (2 x 50 ml), and then significantly acidified with about 30 ml 2N HCl. And extracted with 150ml ethyl acetate (3 x 50ml). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness (40°C) to give a clear thick yellow oil which was used directly in the next step. Yield: 18.5 g, about 100% by mole, about 132% by weight; TLC: dichloromethane/methanol 90/10<; R _f =0.88. The protection of the amino group can also be obtained with ethyl chloroformate by the same procedure with similar results. Example 4 4-[2-(2,3-dimethoxyphenyl)-ethyl]-N-methyl-2,5- oxazolidinedione

Put 18.5g of 4-(2,3-dimethoxyphenyl)-2-(N-methyl-N-benzyloxycarbonyl-amino)-butyric acid (0.048mol) and 28.7g of thionyl chloride into 250ml In a round bottom flask, reflux for 2 hours, then distill off thionyl chloride under vacuum until a thick oil is obtained. The oil was taken out in 100ml of hexane, stirred until solidified, after which it was decanted and triturated with 100ml more hexane, filtered and dried under vacuum at 30°C to give a fine crystalline powder. Yield: 12.5 g, 93% by mole, 68% by weight. Example 5 5,6-dimethoxy-2-methylamino-1-tetralone hydrochloride

Under a nitrogen atmosphere, put 12.5 g of anhydrous aluminum chloride (0.094 mol) in 200 ml of dichloromethane into a 3-liter round bottom flask, cool to 0°C, and dissolve in 200 ml of dichloromethane in about 10 minutes. 4-[2-(2,3-Dimethoxyphenyl)-ethyl]-N-methyl-2,5-oxazolidinedione in methane was added keeping T<10°C. The mixture was stirred at T<10°C for 30 minutes, then at room temperature for 1 hour. The mixture was cooled to 0°C again, and 200ml of water was added dropwise thereto, keeping T<20°C, after which the mixture was stirred at room temperature for about 1 hour, and the organic phase was separated and extracted with water (3×400ml). The combined aqueous phases were slowly basified with 400 ml of 20% KHCO ₃ solution and extracted with 3 x 400 ml of chloroform. Afterwards, the organic phase was dried over sodium sulfate, filtered and evaporated to dryness to obtain a waxy compound, which was taken out into 150 ml of acetone at 50° C., stirred for 1 hour and allowed to stand overnight, then filtered and dried under vacuum at room temperature . Yield: 8.2 g, 67 mol %; TLC: dichloromethane/methanol, 90/10; _Rf = 0.35; MP = 208-209°C. Example 6 5,6-dimethoxy-2-methylamino-1,2,3,4-tetralin hydrochloride

Put 14.0g of 5,6-dimethoxy-2-methylamino-1-tetralone hydrochloride (0.051mol), 400ml of absolute ethanol, 10ml of 1M methanolic HCl and 4.0g of 5% Pd/c into an autoclave (50% humidity) and then hydrogenate the mixture by stirring for 24 hours (pressure P about 7 atm, T=80° C.). The mixture was washed and the filter cake was washed thoroughly with hot methanol. The ethanol solution was then evaporated to dryness. The resulting solid was taken up in 150 ml of acetone, after which the precipitate was filtered and dried under vacuum at 60°C. Yield: 10.8 g, 82% by mole, 77% by weight; M.P. = 219-220°C. Example 75, 6-dihydroxy-2-methylamino-1,2,3,4-tetralin·HCl

41.4 g of dry AlCl ₃ (310.4 mol), 230 ml of toluene and 20.0 g of 5,6-dimethoxy-2-methylamino-1,2,3,4-tetrahydrogenated with stirring under a weak stream of dry nitrogen Naphthalene HCl (77.6 mol) was placed in a 4 neck round bottom flask. Raising the temperature to 80°C gave a stirrable brown mixture which was left at 80°C for 4 hours before being cooled to room temperature and poured into ice water (total amount about 1000ml). The aqueous phase was separated and evaporated under vacuum (T about 80°C). The off-white solid was triturated in 750 ml of absolute ethanol at room temperature and then dried at 60°C. Yield: 16.1 g, 90% by mole, 80% by weight; MP>280°C. Example 8 5,6-dihydroxy-2-methylamino-1-tetralone hydrobromide (bromidrato)

A mixture of 15.0 g of acidic 2-methylamino-4-(2,3-dimethoxyphenyl)-butyric acid hydrochloride (52 mmol) and 100.0 ml of 48% aqueous HBr (900 mmol) was refluxed for 3 hours with stirring , after cooling to 0°C, the resulting precipitate was recovered by filtration, washed with acetone (50 ml) and dried at 60°C under vacuum. Yield: 13.5 g; TLC: CH ₂ Cl ₂ /CH ₃ OH/CH ₃ COOH 70/20/10 (FeCl ₃ /K ₃ Fe(CN) ₆ ); MP: 240-243°C. Example 9 5,6-dihydroxy-2-methylamino-1,2,3,4-tetralin hydrochloride

In an autoclave (Hasterloy) (20atm., 80°C), 10.0g of 5,6-dihydroxy-2-methylamino-1-tetralone hydrobromide, 2.0g of Pd A mixture of /C 5%, 90 ml water and 10 ml 37% HCl was hydrogenated for 8-9 hours, then the filtrate was washed with hot water. The aqueous solution was concentrated in vacuo and the resulting solid was triturated hot with 100 ml of 37% hydrochloric acid before being cooled to 0°C and filtered. The resulting solid was recrystallized from acetone and dried under vacuum at 60°C. Yield: 7.4 g. Example 10 3-methoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5- dihydrofuran - 2-one

Put 300g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid, 860ml of toluene, 13.4g of p-toluenesulfonic acid and 133.8g of methyl carbamate in an oil bath In a 6-liter 4-necked round-bottom flask, the mixture was heated to 105°C with stirring for 4 hours; the remaining water was removed by azeotropy, the mixture was filtered, and the solution was evaporated to dryness under vacuum, and then used with 1260ml The residue was triturated with _Et2O for about 2 hours, the residue was filtered, the filtrate was washed with petroleum ether (40-70°C) and dried under vacuum at 60°C. 313.00 g of product were obtained. (94% yield). Example 11 2-methoxycarbonylamino-4-(2,3-dimethoxyphenyl)butanoic acid

Put 150g of 3-methoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one and 1190ml _CH3OH in a parr hydrogenator 2000ml flask, then heated with stirring until completely dissolved (T about 64°C); add 30g 5% Pd/C, start hydrogenation at 35psi until no more _H2 uptake (about 60 minutes). The disappearance of the starting compound was checked by TLC, after which the mixture was filtered through Celite (diatomaceous earth) and the filtrate was evaporated to dryness, the resulting oil was precipitated by adding diethyl ether and petroleum ether with stirring, stirring was continued for about 30 minutes, and then The mixture was filtered and dried under vacuum at 60°C. 141.6 g of product were obtained. (Yield: 93%). Example 12 2-methoxycarbonylamino-5,6-dimethoxy-1-tetralone

610g polyphosphoric acid is put into 5000ml reactor, is heated to 60 ℃, afterwards, adds 61g 2-methoxycarbonylamino-4-(2,3-dimethoxyphenyl)-butyric acid with strong mechanical stirring. After 20 minutes, the stirred mixture was diluted with water (2000ml) and stirring was continued for 60 minutes at room temperature. The resulting mixture was filtered and the solid was dissolved in 3000ml chloroform. The resulting solution was washed with water until the washings were at neutral pH.

The organic phase was dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The light brown solid residue was triturated in 300 ml diethyl ether and 50 ml petroleum ether for about 2 hours before being filtered and dried under vacuum at 60°C to give a powdery yellow brown solid. Yield: 51.2 g, 89.5 mol%, 84.0 wt %; TLC: dichloromethane 95-methanol 5; _Rf = 0.95. Example 13 2-methoxycarbonylamino-5,6-dimethoxy-1,2,3,4-tetralin

50 g of 2-methoxycarbonylamino-5,6-dimethoxy-1-tetralone was dissolved in 500 ml of methanol in a 1000 ml flask with stirring, 20 g of 5% Pd/C was added and the whole was put Into an autoclave (Hastelloy) under a hydrogen atmosphere of 80° C. and a pressure of 25 atmospheres, with stirring, to react for 6 hours, and then cool the mixture to about 30° C. in the autoclave. The mixture was filtered through Celite (diatomaceous earth) and the filtrate was evaporated to dryness under vacuum. The resulting white solid was triturated in 400 ml of n-hexane at 60°C, then cooled to about 30°C with stirring, filtered and dried under vacuum at 60°C to give a slightly white solid. Yield: 40.6 g, 85.5 mol%, 81.2 wt %; TLC: dichloromethane 95-methanol 5; _Rf = 0.76; MP = 108.7-111.4°C. Example 14 5,6-dimethoxy-2-methylamino-1,2,3,4-tetralin hydrochloride

Put 13.5g of lithium aluminum hydride and 250ml of anhydrous tetrahydrofuran into a 1000ml round bottom flask and stir for 15 minutes, then slowly add 80g of 2-methoxycarbonylamino-5,6-dimethoxy in 350ml of anhydrous tetrahydrofuran dropwise 1,2,3,4-tetralin to maintain the temperature at about 60°C. Stirring was continued for 15 minutes, and the mixture was filtered. The filtrate was cooled to about 0°C and water (1000ml) was added with stirring, maintaining the temperature at about 30°C. The reaction mixture was filtered and extracted with chloroform, the organic phase was dried over sodium sulfate, the filtered organic phase was dried over sodium sulfate, filtered and acidified with methanolic HCl. The resulting solution was stirred for about 30 minutes before being evaporated to dryness. The resulting residue was triturated in 350 ml of acetonitrile at 60°C, cooled to about 4°C with stirring, then filtered and dried under vacuum at 50°C to give a white solid. Yield: 40.7 g, 52.4 mole %, 50.9 weight %. Example 15 5,6-dihydroxy-2-methylamino-1,2,3,4-tetralin hydrochloride

A suspension of 2-methylamino-5,6-dihydroxy-1,2,3,4-tetralin (5 g) in water (45 ml) was added to potassium carbonate (2.5 g) saturated with sodium sulfate aqueous solution (25ml). The mixture was stirred for a few minutes and the solid formed was filtered and washed with some water and acetone before drying under vacuum at room temperature to give 3.8 g of product.

¹ H-NMR (DMSO-d6): 1.40ppm (m, 1H, H3ax), 1.95 (m, 1H, H3eq), 2.40 (s, 3H, N-Me), 2.3-3.0 (m, 5H, H4, H2, H1), 5.0-6.0 (br, 2H, Or-H), 6.45 (d, 1H, H7), 6.56 (d, 1H, H8).

EI/MS (70ev): m/ and 193 (M ⁺ ). Example 16 a) (-)-2-methoxycarbonylamino-4-(2,3-dimethoxyphenyl)-butanoic acid

3-Methoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one (500mg, 1.7mmol) in oxygen-free methanol (0.25M) ) solution into the Parr hydrogenator, adding the catalyst, namely with 1,5-cyclooctadiene and 1,1'-(1,2-phenylene)bis[2,5-diethyl] The 4-(methylphenyl) rhodium sulfonate compound [(SS)-EtDiPhosRh(COD)OTs] (1.5 (μmol) of diphospholane (S, S) is then placed at room temperature under hydrogen pressure (30psi). The mixture was stirred for 1.5 hours.

The mixture was filtered and the filtrate was evaporated in vacuo to give about 500 mg of product (% e.e (NMR=95)).

The product was further purified by crystallization.

NMR analysis (300 Hz, CDCl ₃ , in the presence of R(+)-2-methoxy-α-trifluoromethylphenylacetic acid at 3,842 ppm ((-) enantiomer) and 3,838 ppm ((+ ) enantiomer). (b) (+)-2-methoxycarbonylamino-4-(2,3-dimethoxyphenyl)-butanoic acid

3-Methoxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one (500mg, 1.7mmol) in oxygen-free methanol (0.25M) ) solution into the Parr hydrogenator, adding the catalyst, namely with 1,5-cyclooctadiene and 1,1'-(1,2-phenylene)bis[2,5-diethyl] The 4-(methylphenyl) rhodium sulfonate compound [(RR)-EtDiPhosRh(COD)OTs] (1.5 (μmol) of diphospholane (R, R) is then placed at room temperature under hydrogen pressure (30psi). The mixture was stirred for 1.5 hours.

The mixture was filtered and the filtrate was evaporated under vacuum to give 500 mg of product (% e.e (NMR) = 92).

The product was further purified by crystallization.

NMR analysis (300Hz, CDCl ₃ , in the presence of R(+)-α-methoxy-α-trifluoromethylphenylacetic acid, at 3,842 ppm ((-) enantiomer) and 3,838 ((+) enantiomer) at the signal). Example 17 (+)-2-amino-4-(2,3-dimethoxyamino)-butyric acid

3-Benzyloxycarbonylamino-5-(2,3-dimethoxyphenyl)-2,5-dihydrofuran-2-one (500mg, 1.35mmol) in oxygen-free methanol (0.25M) ) solution into the Parr hydrogenator, adding the catalyst, namely with 1,5-cyclooctadiene and 1,1'-(1,2-phenylene)bis[2,5-diethyl] The 4-(methylphenyl) rhodium sulfonate compound [(RR)-EtDiPhosRh(COD)OTs] (1.3 (μmol) of diphospholane (R, R), then under hydrogen pressure (30psi) at room temperature The mixture was stirred for 3 hours.

The mixture was filtered and the filtrate was evaporated in vacuo to give 320 mg of product (% e.e (NMR) = 75)).

The product was further purified by crystallization. NRM analysis was performed: signals at 3.34 ppm ((-) enantiomer) and 3.22 ppm ((+) enantiomer).

Claims (4)

1. one kind prepares 5, the method for 6-dihydroxyl-2-amino-1,2,3,4-tetralin, and this method comprises the following steps:

(a) with 4-(2,3-dialkoxy phenyl)-2-oxygen-3-butenoic acid with the benzyl carbamate condensation, obtain 3-benzyloxycarbonyl amino-5-(2, the 3-alkoxyl phenyl)-2,5-dioxy furans-2-ketone;

(b) protection is also removed nitrogen in reduction simultaneously, obtains 2-amino-4-(2,3-dialkoxy phenyl) butyric acid;

(c) protection is also removed the catechol hydroxyl in cyclisation simultaneously, obtains 5,6-dihydroxyl-2-amino-1-Tetralone an intermediate of Sertraline;

(d) with this ketone reduction, obtain 5,6-dihydroxyl-2-amino-1,2,3,4-tetralin.

2. the process of claim 1 wherein that step (c) contains hydracid with halo and finishes.

3. the process of claim 1 wherein that step (d) undertaken by asymmetric hydrogenization, obtain 2-amino-4-(2,3-dialkoxy phenyl) butyric acid of optically-active.

4. the method for claim 1-8, R wherein ₁It is methyl.